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Genetic and pharmacological modulation of the steroid sulfatase axis improves response control; comparison to drugs used in ADHD

Davies, William, Humby, Trevor, Trent, Simon, Eddy, Jessica B., Ojarikre, Obah A. and Wilkinson, Lawrence Stephen 2014. Genetic and pharmacological modulation of the steroid sulfatase axis improves response control; comparison to drugs used in ADHD. Neuropsychopharmacology 39 (11) , pp. 2622-2632. 10.1038/npp.2014.115

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Abstract

Maladaptive response control is a feature of many neuropsychiatric conditions, including Attention Deficit Hyperactivity Disorder (ADHD). As ADHD is more commonly diagnosed in males than females, a pathogenic role for sex-linked genes has been suggested. Deletion or point mutation of the X-linked STS gene, encoding the enzyme steroid sulfatase influences risk for ADHD. We examined whether deletion of the Sts gene in the 39,XY*O mouse model, or pharmacological manipulation of the steroid sulfatase axis, via administration of the enzyme substrate dehydroepiandrosterone sulfate or the enzyme inhibitor COUMATE, influenced behavior in a novel murine analogue of the stop-signal reaction time task used to detect inhibitory deficits in individuals with ADHD. Unexpectedly, both the genetic and pharmacological treatments resulted in enhanced response control, manifest as highly specific effects in the ability to cancel a pre-potent action. For all three manipulations, the effect size was comparable to that seen with the commonly used ADHD therapeutics methylphenidate and atomoxetine. Hence, converging genetic and pharmacological evidence indicate that the steroid sulfatase axis is involved in inhibitory processes and can be manipulated to give rise to improvements in response control. Whilst the precise neurobiological mechanism(s) underlying the effects remain to be established, there is the potential for exploiting this pathway in the treatment of disorders where failures in behavioral inhibition are prominent.

Item Type: Article
Date Type: Publication
Status: Published
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Medicine
Neuroscience and Mental Health Research Institute (NMHRI)
Psychology
Subjects: B Philosophy. Psychology. Religion > BF Psychology
R Medicine > R Medicine (General)
Additional Information: Pdf uploaded in accordance with publisher's policy at http://www.sherpa.ac.uk/romeo/issn/0893-133X/ (accessed 22/05/2014)
Publisher: Nature Publishing Group
ISSN: 0893-133X
Funders: MRC
Date of First Compliant Deposit: 30 March 2016
Last Modified: 02 May 2019 13:09
URI: http://orca.cf.ac.uk/id/eprint/59610

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